The Gofman-Tamplin Cancer Risk Controversy and Its Impact on the Creation of BEIR I and the Acceptance of LNT.

BACKGROUND:  The major public dispute between John Gofman and his colleague Arthur Tamplin and the United States (US) Atomic Energy Commission (AEC) at the end of the 1960s and during the early 1970s significantly impacted the course of cancer risk assessment in the US and worldwide. The challenging and provocative testimony of Gofman to the US Senate in early 1970 lead to the formation of the US National Academy of Sciences (NAS) Biological Effects of Ionizing Radiation (BEIR) I Committee in order to evaluate the accuracy of claims by Gofman and Tamplin that emissions from nuclear power plants would significantly increase the occurrence of genetic defects and cancers. BEIR I recommended the adoption of the linear non-threshold (LNT) dose response model for the assessment of cancer risks from radiation exposures. The US EPA adopted this recommendation and generalized it to incorporate chemical carcinogens, thereby affecting cancer risk assessments over the next decades. Despite the scientific limitations and ideological framework of their perspectives, Gofman and Tamplin are of considerable historical importance since they had essential roles in affecting the adoption of LNT by regulatory agencies.

Linear Non-Threshold (LNT) historical discovery milestones.

The present paper provides a summarized identification of critical historical milestones in the discovery of the flawed and corrupt foundations of cancer risk assessment, with particular focus on the LNT Dose Response model. The milestone sequence presented herein is based on a large body of published findings by the author. The history of LNT and cancer response represents what may be the most significant case of scientific misconduct reported in the US, with its revelation severely damaging the scientific credibility and moral authority of leading US regulatory agencies and organizations such as the National Academy of Sciences (NAS) and the journal Science. The consequences of this corrupt history are substantial, affecting cancer risk assessment throughout the world, critical aspects of national economies, the development of critical technologies and public health practices.

Ethical Issues in the US 1956 National Academy of Sciences BEAR I Genetics Panel Report to the Public.

ABSTRACT: This paper presents newly discovered evidence from the personal correspondence of four US National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) Genetics Panelists that their 1956 report to the public was written by a third party and was neither reviewed nor approved by the Panel prior to its publication and release to the public. The letters revealed that the 1956 Report contained serious errors and did not represent the views of the Panel. The failure of the US NAS to notify the public that the Report had not been reviewed and approved by the Panel represents a serious breach of ethics. Further ethical issues relate to the failure of the NAS to (1) correct the errors in the Report within an appropriately timely manner and (2) reveal the lack of approval by the Panel even after the Report's release. In light of these discoveries and the profound historical-and continuing-significance of the 1956 Report to all conventional cancer-related risk assessment processes, we opine that this ethical improbity must be acknowledged and that this document must be retracted by the NAS.

Leveraging Integrated Primary Care to Address Patients' and Families' Unmet Social Needs: Aligning Practice with National Academy of Sciences, Engineering and Medicine Recommendations.

Primary care is well-poised to address unmet social needs that affect health. Integrated primary care is increasingly common and can be leveraged to facilitate identification of practice and clinician-level modifiable characteristics and assist practices to address unmet social needs for patients and families. A recent National Academies of Sciences, Engineering, and Medicine (NASEM)'s consensus report identified 5 critical system-level activities to facilitate the integration of addressing social needs into health care: awareness (ask patients), adjustment (flexible intervention delivery), assistance (intervention to address the social need), alignment (link with community resources), and advocacy (policy change). This article outlines how integrated primary care characteristics, such as routine screening, functional workflows, interprofessional team communication, and patient-centered practices, exemplify the NASEM report's activities and offer robust biopsychosocial tools for addressing social needs. We provide a case to illustrate how these strategies might be used in practice.

Ethical failings: The problematic history of cancer risk assessment.

This paper demonstrates that unethical conduct by the US National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel led to their recommendation of the Linear Non-Threshold (LNT) Model for radiation risk assessment and its subsequent adoption by the US and the world community. The analysis, which is based largely on preserved communications of the US NAS Genetics Panel members, reveals that Panel members and their administrative leadership at the NAS displayed an integrated series of unethical actions designed to ensure, (1) the acceptance of the LNT and (2) funding to radiation geneticist panel members and professional colleagues. These findings are significant because major public policies in open democracies, such as cancer risk assessment and other issues impacted by public fears of radiation or chemical exposures, require ethical foundations. Recognition of these ethical failures of the BEAR I Genetics Panel should require a high level administrative, legislative and scientific reassessment of the scientific foundations of cancer risk assessment, with the likely result necessitating revision of current policies and practices. The BEAR I Genetics Panel, 1956 Science journal publication should immediately be retracted because it contains deliberate misrepresentations of the scientific record that were designed to manipulate scientific and public opinion on radiation risk assessment in a dishonest manner.

The Muller-Neel dispute and the fate of cancer risk assessment.

The National Academy of Sciences (NAS) Atomic Bomb Casualty Commission (ABCC) human genetic study (i.e., The Neel and Schull, 1956a report) showed an absence of genetic damage in offspring of atomic bomb survivors in support of a threshold model, but was not considered for evaluation by the NAS Biological Effects of Atomic Radiation (BEAR) I Genetics Panel. The study therefore could not impact the Panel's decision to recommend the linear non-threshold (LNT) dose-response model for risk assessment. Summaries and transcripts of the Panel meetings failed to reveal an evaluation of this study, despite its human relevance and ready availability, relying instead on data from Drosophila and mice. This paper explores correspondence among and between BEAR Genetics Panel members, including James Néel, the study director, and other contemporaries to assess why the Panel failed to use these data and how the decision to recommend the LNT model affected future cancer risk assessment policies and practices. This failure of the Genetics Panel was due to: (1) a strongly unified belief in the LNT model among panel members and their refusal to acknowledge that a low dose of radiation could exhibit a threshold, a conclusion that the Néel/Schull atomicbomb study could support, and (2) an excessive degree of self-interest among panel members who experimented with animal models, such as Hermann J. Muller, and feared that human genetic studies would expose the limitations of extrapolating from animal (especially Drosophila) to human responses and would strongly shift research investments/academic grants from animal to human studies. Thus, the failure to consider the Néel/Schull atomic bomb study served both the purposes of preserving the LNT policy goal and ensuring the continued dominance of Muller and his similarly research-oriented colleagues.

Avaliação do modelo NRC para predição do consumo de matéria seca por vacas leiteiras manejadas em pastos tropicais / NCR Model Evaluation for prediction of dry matter intake by dairy cows managed in tropical pastures

Objetivou-se avaliar o poder preditivo do modelo do National Research Council (NRC) para gado leiteiro em estimar o consumo de matéria seca (CMS) por vacas mestiças, em pastagens tropicais. Foi efetuada uma análise conjunta de cinco estudos, contemplando três forrageiras. Foram avaliadas 132 estimativas individuais do CMS observado (CMSObs), obtidas por meio do indicador externo Cr2O3. O CMS também foi predito por meio do software do NRC (CMSPred), que, por sua vez, foi abastecido com inputs referentes aos animais e ao ambiente de criação. Os valores de CMSPred (12,7±1,6kg/d) foram semelhantes aos de CMSObs (12,3±3,3kg/d). Foram obtidas as seguintes estimativas da avaliação do poder preditivo do modelo: viés médio (-0,419kg/d), coeficiente de determinação (0,029), coeficiente de correlação (0,17; P=,051), quadrado médio do erro de predição (11,844±20,034), fator de eficiência do modelo (-0,081), coeficiente de determinação do modelo (4,1032) e fator de correção do viés (0,767). A comparação entre CMSObs e CMSPred permitiu identificar a tendência de superestimação das predições se considerado o ajuste por meio de regressão robusta para o modelo linear simples sem intercepto. Nas condições avaliadas, o modelo produz predições de CMS com satisfatória exatidão, porém com baixa precisão.(AU)

The aim of the present study was to evaluate the predictive power of estimating the dry matter intake (DMI) of crossbred cows on tropical pastures by the National Research Council (NRC) equation for dairy cattle. A joint analysis of five studies covering three forages was performed in which 132 individual estimates of observed DMI obtained through Cr2O3 as a marker. DMI was also predicted from the NRC (DMIPred) software with inputs concerning animals and breeding environment of the studies used. Predicted DMIPred average values (12.7±1.6kg/d) were similar to the observed DMIObs ones (12.3±3.3kg/d). We obtained the following estimates of the evaluation of the predictive power of the model: average bias (- 0.419kg/d), coefficient of determination (0.029), Person's correlation coefficient (0.17, P= 0.051), mean square error of prediction (11,844±20,034), model efficiency factor (- 0.081), coefficient of determination (4.1032), and bias correction factor (0.767). The comparison between DMIObs and DMIPred values allowed the identification of the overestimating tendency of the predictions demonstrated by the robust regression fit of the simple linear no intercept model. Nevertheless, the model yields predictions with satisfactory accuracy, but with low precision.(AU)

Toxicity testing in the 21st century: progress in the past decade and future perspectives.

Advances in the biological sciences have led to an ongoing paradigm shift in toxicity testing based on expanded application of high-throughput in vitro screening and in silico methods to assess potential health risks of environmental agents. This review examines progress on the vision for toxicity testing elaborated by the US National Research Council (NRC) during the decade that has passed since the 2007 NRC report on Toxicity Testing in the 21st Century (TT21C). Concomitant advances in exposure assessment, including computational approaches and high-throughput exposomics, are also documented. A vision for the next generation of risk science, incorporating risk assessment methodologies suitable for the analysis of new toxicological and exposure data, resulting in human exposure guidelines is described. Case study prototypes indicating how these new approaches to toxicity testing, exposure measurement, and risk assessment are beginning to be applied in practice are presented. Overall, progress on the 20-year transition plan laid out by the US NRC in 2007 has been substantial. Importantly, government agencies within the United States and internationally are beginning to incorporate the new approach methodologies envisaged in the original TT21C vision into regulatory practice. Future perspectives on the continued evolution of toxicity testing to strengthen regulatory risk assessment are provided.

From Muller to mechanism: How LNT became the default model for cancer risk assessment.

This paper summarizes the historical and scientific foundations of the Linear No-Threshold (LNT) cancer risk assessment model. The story of cancer risk assessment is an extraordinary one as it was based on an initial incorrect gene mutation interpretation of Muller, the application of this incorrect assumption in the derivation of the LNT single-hit model, and a series of actions by leading radiation geneticists during the 1946-1956 period, including a National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel (Anonymous, 1956), to sustain the LNT belief via a series of deliberate obfuscations, deceptions and misrepresentations that provided the basis of modern cancer risk assessment policy and practices. The reaffirming of the LNT model by a subsequent and highly influential NAS Biological Effects of Ionizing Radiation (BEIR) I Committee (NAS/NRC, 1972) using mouse data has now been found to be inappropriate based on the discovery of a significant documented error in the historical control group that led to incorrect estimations of risk in the low dose zone. Correction of this error by the original scientists and the application of the adjusted/corrected data back to the BEIR I (NAS/NRC, 1972) report indicates that the data would have supported a threshold rather than the LNT model. Thus, cancer risk assessment has a poorly appreciated, complex and seriously flawed history that has undermined policies and practices of regulatory agencies in the U.S. and worldwide to the present time.

The need for transparency and reproducibility in documenting values for regulatory decision making and evaluating causality: The example of formaldehyde.

Reproducibility and transparency in scientific reporting is paramount to advancing science and providing the foundation required for sound regulation. Recent examples demonstrate that pivotal scientific findings cannot be replicated, due to poor documentation or methodological bias, sparking debate across scientific and regulatory communities. However, there is general agreement that improvements in communicating and documenting research and risk assessment methods are needed. In the case of formaldehyde, the peer-review conducted by a National Academy of Sciences (NAS) Committee questioned the approaches used by the Integrated Risk Information System (IRIS) in developing draft unit risk values. Using the original data from the key study (Beane Freeman et al., 2009) and documentation provided in the draft IRIS profile, we attempted to duplicate the reported inhalation unit risk values and address the NAS Committee's questions regarding application of the appropriate dose-response model. Overall, documentation of the methods lacked sufficient detail to allow for replication of the unit risk estimates, specifically for Hodgkin lymphoma and leukemias, the key systemic endpoints selected by IRIS. The lack of apparent exposure-response relationships for selected endpoints raises the question whether quantitative analyses are appropriate for these endpoints, and if so, how results are to be interpreted.

Response to, "On the origins of the linear no-threshold (LNT) dogma by means of untruths, artful dodges and blind faith.".

It is not true that successive groups of researchers from academia and research institutions-scientists who served on panels of the US National Academy of Sciences (NAS)-were duped into supporting a linear no-threshold model (LNT) by the opinions expressed in the genetic panel section of the 1956 "BEAR I" report. Successor reports had their own views of the LNT model, relying on mouse and human data, not fruit fly data. Nor was the 1956 report biased and corrupted, as has been charged in an article by Edward J. Calabrese in this journal. With or without BEAR I, the LNT model would likely have been accepted in the US for radiation protection purposes in the 1950's.

The Molecular Pharmacology of G Protein Signaling Then and Now: A Tribute to Alfred G. Gilman.

The recent, unfortunate death of Alfred G. ("Al") Gilman, M.D., Ph.D., represents a sad signpost for an era spanning over 40 years in molecular pharmacology. Gilman's discoveries, influence, and persona were dominant forces in research and training in pharmacology. Here, we review the progression of ideas and knowledge that spawned early work by Gilman and collaborators (among them, one of the authors) and later efforts (including those of the other author) that have recently yielded a comprehensive and precise structural understanding of fundamental topics in pharmacology: the binding of ligands to G protein-coupled receptors (GPCRs) and the interaction of GPCRs with heterotrimeric G proteins and effector molecules. Those data provide new and important insights into the molecular basis that underlies affinity and efficacy, two of the most important features of drug action, which represent the latest chapter in the saga that Al Gilman's work helped launch.

On the origins of the linear no-threshold (LNT) dogma by means of untruths, artful dodges and blind faith.

This paper is an historical assessment of how prominent radiation geneticists in the United States during the 1940s and 1950s successfully worked to build acceptance for the linear no-threshold (LNT) dose-response model in risk assessment, significantly impacting environmental, occupational and medical exposure standards and practices to the present time. Detailed documentation indicates that actions taken in support of this policy revolution were ideologically driven and deliberately and deceptively misleading; that scientific records were artfully misrepresented; and that people and organizations in positions of public trust failed to perform the duties expected of them. Key activities are described and the roles of specific individuals are documented. These actions culminated in a 1956 report by a Genetics Panel of the U.S. National Academy of Sciences (NAS) on Biological Effects of Atomic Radiation (BEAR). In this report the Genetics Panel recommended that a linear dose response model be adopted for the purpose of risk assessment, a recommendation that was rapidly and widely promulgated. The paper argues that current international cancer risk assessment policies are based on fraudulent actions of the U.S. NAS BEAR I Committee, Genetics Panel and on the uncritical, unquestioning and blind-faith acceptance by regulatory agencies and the scientific community.

Evaluating the influence of National Research Council levels of copper, iron, manganese, and zinc using organic (Bioplex) minerals on resulting tissue mineral concentrations, metallothionein, and liver antioxidant enzymes in grower-finisher swine diets.

Graded levels of a trace mineral premix containing an organic (Bioplex) source of Cu, Fe, Mn, and Zn was evaluated with additional treatments containing organic Zn or Fe. Grower-finisher pigs were fed from 25 to 115 kg BW. The number of pigs in the experiment, the breeding/genetics of the pigs, the management, and the average age of the pigs were previously reported. The experiment was conducted as a randomized complete block design in 7 replicates. Treatments were 1) basal diet without supplemental Cu, Fe, Mn, and Zn; 2) basal diet + 2.5 mg/kg Cu, 50 mg/kg Fe, 1.5 mg/kg Mn, and 40 mg/kg Zn (50% NRC); 3) basal diet + 5 mg/kg Cu, 100 mg/kg Fe, 3 mg/kg Mn, and 80 mg/kg Zn (100% NRC); 4) basal diet + 25 mg Zn/kg; 5) basal diet + 50 mg Zn/kg; and 6) basal diet + 50 mg Fe/kg. Selenium and I were added to all diets at 0.3 and 0.14 mg/kg, respectively. Diets were composed of corn-soybean meal, dicalcium phosphate, and limestone with phytase added to enhance mineral availability. Three pigs per pen were bled at 55, 80, and 115 kg BW and plasma was analyzed for microminerals. When the average replicate BW was 115 kg, 3 pigs per pen of an equal gender ratio were killed. The liver, kidney, and heart were removed and analyzed for microminerals. Liver, duodenum, and jejunal metallothionein and the antioxidant enzymes in the liver containing these microminerals were determined. The results demonstrated that plasma minerals were unaffected at the 3 BW intervals. Liver and duodenum metallothionein protein were greater ( < 0.05) as dietary micromineral levels increased but jejunum metallothionein did not change as microminerals increased. The activity of Cu/Zn superoxide dismutase (SOD) was not affected as the levels of the micromineral increased, whereas the activity of Mn SOD increased slightly ( < 0.05) to the 50% NRC treatment level. Liver Zn (relative and total) increased ( < 0.05) as dietary micromineral levels increased and also when Zn was added singly to the diet. Liver, kidney, and heart Cu and Mn concentrations were similar at the various micromineral levels. The activities of liver enzymes containing graded levels of Zn were not affected by dietary microminerals at 115 kg BW. These results indicate that the supplemental levels of Cu, Fe, and Mn were not necessary for grower-finisher pigs and that these innate microminerals in a corn-soybean meal diet were adequate, whereas a need for supplemental Zn was demonstrated.

An abuse of risk assessment: how regulatory agencies improperly adopted LNT for cancer risk assessment.

The Genetics Panel of the National Academy of Sciences' Committee on Biological Effects of Atomic Radiation (BEAR) recommended the adoption of the linear dose-response model in 1956, abandoning the threshold dose-response for genetic risk assessments. This recommendation was quickly generalized to include somatic cells for cancer risk assessment and later was instrumental in the adoption of linearity for carcinogen risk assessment by the Environmental Protection Agency. The Genetics Panel failed to provide any scientific assessment to support this recommendation and refused to do so when later challenged by other leading scientists. Thus, the linearity model used in cancer risk assessment was based on ideology rather than science and originated with the recommendation of the NAS BEAR Committee Genetics Panel. Historical documentation in support of these conclusions is provided in the transcripts of the Panel meetings and in previously unexamined correspondence among Panel members.

Cancer risk assessment foundation unraveling: new historical evidence reveals that the US National Academy of Sciences (US NAS), Biological Effects of Atomic Radiation (BEAR) Committee Genetics Panel falsified the research record to promote acceptance of the LNT.

The NAS Genetics Panel (1956) recommended a switch from a threshold to a linear dose response for radiation risk assessment. To support this recommendation, geneticists on the panel provided individual estimates of the number of children in subsequent generations (one to ten) that would be adversely affected due to transgenerational reproductive cell mutations. It was hoped that there would be close agreement among the individual risk estimates. However, extremely large ranges of variability and uncertainty characterized the wildly divergent expert estimates. The panel members believed that sharing these estimates with the scientific community and general public would strongly undercut their linearity recommendation, as it would have only highlighted their own substantial uncertainties. Essentially, their technical report in the journal Science omitted and misrepresented key adverse reproductive findings in an effort to ensure support for their linearity recommendation. These omissions and misrepresentations not only belie the notion of an impartial and independent appraisal by the NAS Panel, but also amount to falsification and fabrication of the research record at the highest possible level, leading ultimately to the adoption of LNT by governments worldwide. Based on previously unexamined correspondence among panel members and Genetics Panel meeting transcripts, this paper provides the first documentation of these historical developments.